The most toxic of the dioxin compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which was the primary dioxin component of "Agent Orange" and has been found at numerous toxic waste sites. Probably all persons living in industrialized countries have been exposed to TCDD via the food supply, especially meats, eggs, and dairy products. TCDD has a high solubility in lipid and a half-life estimated to be between 7 to 9 years in humans. Several studies involving industrial exposure have reported an association between TCDD and various components of impaired carbohydrate metabolism. Epidemiological studies of Air Force veterans who were part of Operation Ranch Hand (the unit responsible for aerial spraying of Agent Orange in Vietnam) demonstrated an association between TCDD levels and diabetes. In addition, non-diabetic veterans with high blood TCDD levels were more likely to be hyperinsulinemic. The greater prevalence of hyperinsulinemia in non-diabetic subjects suggested that the hyperinsulinemia was the result of insulin resistance. This project will examine the role of environmental dioxin exposure in the development of insulin-resistance, a pre-diabetic state in which normal blood glucose levels are maintained by high circulating levels of insulin. The objectives of this project are the further document this pathology in humans and to determine the mechanisms of the toxic effects in an animal model.